title: Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies.
abstract: The anti-CD20 mAb rituximab has substantially improved the clinical outcome of patients with a wide range of B-cell malignancies. However, many patients relapse or fail to respond to rituximab, and thus there is intense investigation into the development of novel anti-CD20 mAbs with improved therapeutic efficacy. Although Fc-FcγR interactions appear to underlie much of the therapeutic success with rituximab, certain type II anti-CD20 mAbs efficiently induce programmed cell death (PCD), whereas rituximab-like type I anti-CD20 mAbs do not. Here, we show that the humanized, glycoengineered anti-CD20 mAb GA101 and derivatives harboring non-glycoengineered Fc regions are type II mAb that trigger nonapoptotic PCD in a range of B-lymphoma cell lines and primary B-cell malignancies. We demonstrate that GA101-induced cell death is dependent on actin reorganization, can be abrogated by inhibitors of actin polymerization, and is independent of BCL-2 overexpression and caspase activation. GA101-induced PCD is executed by lysosomes which disperse their contents into the cytoplasm and surrounding environment. Taken together, these findings reveal that GA101 is able to potently elicit actin-dependent, lysosomal cell death, which may potentially lead to improved clearance of B-cell malignancies in vivo.
authors.affiliation: Targeted Therapy Group, Paterson Institute for Cancer Research, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Health Sciences Center, Manchester, UK.
authors.forename: Waleed
authors.initials: W
authors.lastname: Alduaij
authors.forename: Andrei
authors.initials: A
authors.lastname: Ivanov
authors.forename: Jamie
authors.initials: J
authors.lastname: Honeychurch
authors.forename: Eleanor J
authors.initials: EJ
authors.lastname: Cheadle
authors.forename: Sandeep
authors.initials: S
authors.lastname: Potluri
authors.forename: Sean H
authors.initials: SH
authors.lastname: Lim
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Shimada
authors.forename: Claude H T
authors.initials: CH
authors.lastname: Chan
authors.forename: Alison
authors.initials: A
authors.lastname: Tutt
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Beers
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cragg
authors.forename: Tim M
authors.initials: TM
authors.lastname: Illidge
mesh_terms: D000199:Actins / Q000187:drug effects / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002403:Cathepsins / Q000494:pharmacology; D002448:Cell Adhesion / Q000276:immunology; D016923:Cell Death / Q000187:drug effects* / Q000276:immunology*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000276:immunology; D019008:Drug Resistance, Neoplasm / Q000276:immunology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000276:immunology; D000069283:Rituximab
chemical_list: D000199:Actins; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab; D002403:Cathepsins; C543332:obinutuzumab